Methods and Compositions for Modulating Beta-Amyloid/Alpha7-nAChR Interactions

ABSTRACT

Methods of modulating the interaction between β-amyloid and α7-nAChR are provided. Aspects of the methods include administering to the subject an effective amount of a naphthalene derivative active agent. Compositions and kits for practicing the subject methods are also provided. The methods, compositions and kits find use in treating a variety of applications, such as treating a subject for a neurodegenerative disease, e.g., Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATION

Pursuant to 35 U.S.C. § 119 (e), this application claims priority to thefiling date of the U.S. Provisional Patent Application Ser. No.62/482,867, filed Apr. 7, 2017; the disclosure of which application isherein incorporated by reference.

INTRODUCTION

Alzheimer's Disease (AD) is the most common type of dementia and the 6thleading cause of death in USA, affecting over 5.1 million adults overthe age of 65 years in this country, and costing the economy over $150billion per year. AD is a disorder directly impacted by thealpha-7-nicotinic acetylcholine receptor (α-7nAChR) and positiveallosteric modulator (PAM) agonists represent a disease modifying classof compounds that have already been clinically validated. While themechanisms underlying the AD pathophysiology are still partiallyunclear, aggregation of tau and β-amyloid proteins and decreasedacetylcholine are a focus of many studies. To date animal studies ofα-7nAChR PAMs performed in in vivo models of AD and have shownimprovement in cognition as well as reduction in brain tau and β-amyloidpathology. Unfortunately, the therapies currently on the market fortreatment of AD, namely four cholinesterase inhibitors and one NMDAinhibitor, are only symptomatic and do not affect the underlying diseasemechanisms or alter the disease course. Consequently, new medicationswith disease modifying effects are desperately needed for this disorder.

Galantamine is a cholinesterase inhibitor used in the treatment of ADthat was later found to have a dual action at the neuronal nicotinicacetylcholine receptor (nAChRs). nAChRs play key roles in modulatingneurotransmission, cognition, anxiety, and sensory gating. Previousstudies have also demonstrated that α7-nAChR in particular may play acentral role in the pathophysiology of AD. The α7-nAChRs are ligandgated ion channels comprised of five alpha7 subunits and function in theregulation of intracellular calcium. By modulating intracellular calciumlevels in discrete neuronal locations they influence numerousphysiological processes in the central nervous system. These receptorsare responsible for regulating pre- and post-synaptic neurotransmitterrelease, regulation of neuronal growth, and regulation of neuronaldifferentiation. Additionally, these receptors serve as a feedbackmechanism modulating glutamatergic pathways. Because α7-nAChR agoniststypically result in tolerance, an alternative approach is to usepositive allosteric modulators (PAMs). Galantamine is also a α7-nAChRPAM and has been shown to slow cognitive and global decline in patientswith AD as well as reduce behavioral symptoms in these patients.However, these effects are not disease modifying and it is not clearthat Galantamine is able to function as an α7-nAChR PAM in people due topreferential functioning through its other mechanism of action as anacetylcholinesterase inhibitor.

PAMs (for which 2 potential types have been proposed) represent a newand potentially disease modifying class of compounds that are stronglysupported by evidence from both in vitro and in vivo studies. Previousstudies demonstrate the ability of α7-nAChR PAM compounds to affect bothβ-amyloid and tau deposition in AD. In AD, β-amyloid has been shown tobind with high affinity to neuronal α7-nAChR and this interaction istheorized to be important in the formation of amyloid plaques.Additionally, when the α7-nAChR is bound by β-amyloid it loses itsnormal functioning and activity, and causes rapid phosphorylation of tauwhich leads to abnormal accumulation and aggregation, followed byformation of the characteristic neurofibrillary tangles found in thisdisorder. When the α7-nAChR subunit is deleted in the mouse model of ADthere is protection of synaptic integrity and relative preservation oflearning and memory functions. It has therefore been suggested thatdisrupting the interaction between β-amyloid and the α7-nAChR is apossible therapeutic target for treating AD.

The α7-nAChR agonists comprise one class of compounds that are known tobe able to disrupt this interaction between β-amyloid and α7-nAChR.Consequently, developing novel agonists that act through this mechanismand are well tolerated is an active area of research for developingpotential new therapeutic agents in AD. Animal models serve as goodpredictors of the effect of a7 nAChR PAMs. For example galantamineslowed down plaque formation and behavioral decline in the 5×FAD mousemodel of AD. This animal overexpresses amyloid precursor protein (APP)with three familial AD (FAD) mutations and the model recapitulatescertain AD features such as memory impairment, plaque formation, reducedanxiety, and neuron loss.

SUMMARY

Methods of modulating the interaction between β-amyloid and α7-nAChR areprovided. Aspects of the methods include administering to the subject aneffective amount of a naphthalene derivative active agent. Compositionsand kits for practicing the subject methods are also provided. Themethods, compositions and kits find use in treating a variety ofapplications, such as treating a subject for a neurodegenerativedisease, e.g., Alzheimer's disease.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: α7-nAChR patch-clamp results for FDA approved compounds andGalantamine Derivatives.

FIG. 2: Comparison of α7-nAChR patch-clamp results for Propranolol andPNU-120596.

FIG. 3: Binding Affinity vs. Location of Propranolol Derivatives.

FIG. 4: Patch-clamp Studies of Structurally Novel PropranololDerivatives A. V2, B V4, C V5, D V6S, E V6R.

DEFINITIONS

Before describing exemplary embodiments in greater detail, the followingdefinitions are set forth to illustrate and define the meaning and scopeof the terms used in the description. Any undefined terms have their artrecognized meanings.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Where compounds described herein contain one or more chiral centersand/or double-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers, all possible enantiomers and stereoisomers of thecompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures are included in thedescription of the compounds herein. Enantiomeric and stereoisomericmixtures can be resolved into their component enantiomers orstereoisomers using separation techniques or chiral synthesis techniqueswell known to the skilled artisan. The compounds can also exist inseveral tautomeric forms including the enol form, the keto form andmixtures thereof. Accordingly, the chemical structures depicted hereinencompass all possible tautomeric forms of the illustrated compounds.The compounds described also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that can beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds canexist in unsolvated forms as well as solvated forms, including hydratedforms. In general, compounds can be hydrated or solvated. Certaincompounds can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplatedherein and are intended to be within the scope of the presentdisclosure.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way ofexample, linear and branched hydrocarbyl groups such as methyl (CH₃—),ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl(CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—),t-butyl ((CH₃)₃C—), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl((CH₃)₃CCH₂—).

The term “substituted alkyl” refers to an alkyl group as defined hereinwherein one or more carbon atoms in the alkyl chain have been optionallyreplaced with a heteroatom such as —O—, —N—, —S—, —S(O)_(n)— (where n is0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, and —NR^(a)R^(b), wherein R′ and R″ may be the same ordifferent and are chosen from hydrogen, optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of an alkene. The group may bein either the cis or trans conformation about the double bond(s). Insome cases, alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of an alkyne. In some cases,alkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclyl-C(O)—, and substitutedheterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. For example, acylincludes the “acetyl” group CH₃C(O)—

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. Theterm “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl,cycloalkenyl, and alkynyl are as defined herein. The term “substitutedalkoxy” refers to the groups substituted alkyl-O—, substitutedalkenyl-O—, substituted cycloalkyl-O—, substituted cycloalkenyl-O—, andsubstituted alkynyl-O— where substituted alkyl, substituted alkenyl,substituted cycloalkyl, substituted cycloalkenyl and substituted alkynylare as defined herein.

“Amino” refers to the group —NH₂. The term “substituted amino” refers tothe group —NRR where each R is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl,heteroaryl, and heterocyclyl provided that at least one R is nothydrogen.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 18 carbon atoms having a single ring (such as is present in aphenyl group) or a ring system having multiple condensed rings (examplesof such aromatic ring systems include naphthyl, anthryl and indanyl)which condensed rings may or may not be aromatic, provided that thepoint of attachment is through an atom of an aromatic ring. This termincludes, by way of example, phenyl and naphthyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, or from 1to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or“carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl,—C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic,wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” or “carbonate” refers to the groups —O—C(O)O—alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl,—O—C(O)O-substituted alkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substitutedalkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl,—O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O—substituted cycloalkenyl, —O—C(O)O-heteroaryl, —O—C(O)O-substitutedheteroaryl, —O—C(O)O-heterocyclic, and —O—C(O)O-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In certainembodiments, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂— moieties.

“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms,such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected fromthe group consisting of oxygen, nitrogen, and sulfur within the ring.Such heteroaryl groups can have a single ring (such as, pyridinyl,imidazolyl or furyl) or multiple condensed rings in a ring system (forexample as in groups such as, indolizinyl, quinolinyl, benzofuran,benzimidazolyl or benzothienyl), wherein at least one ring within thering system is aromatic and at least one ring within the ring system isaromatic, provided that the point of attachment is through an atom of anaromatic ring. In certain embodiments, the nitrogen and/or sulfur ringatom(s) of the heteroaryl group are optionally oxidized to provide forthe N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes,by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, andfuranyl. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can be optionallysubstituted with 1 to 5 substituents, or from 1 to 3 substituents,selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl, andtrihalomethyl.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic, and heterocyclo groups substituted with oneor more groups preferably selected from alkyl, substituted alkyl,alkenyl, oxo, aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo (optionally substituted), halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkanoyl(optionally substituted), aroyl (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), cyano,nitro, amido, amino, substituted amino, lactam, urea, urethane,sulfonyl, and the like, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Sulfonyl” refers to the group SO₂-alkyl, SO₂-substituted alkyl,SO₂-alkenyl, SO₂-substituted alkenyl, SO₂-cycloalkyl, SO₂-substitutedcycloalkyl, SO₂-cycloalkenyl, SO₂-substituted cylcoalkenyl, SO₂-aryl,SO₂-substituted aryl, SO₂-heteroaryl, SO₂-substituted heteroaryl,SO₂-heterocyclic, and SO₂-substituted heterocyclic, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Sulfonyl includes, by way of example, methyl-SO₂—, phenyl-SO₂—,and 4-methylphenyl-SO₂—.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for substituting for one or more hydrogens(any two hydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S) on saturated carbon atoms in the specified group orradical are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—NR⁸⁰R⁸⁰, trihalomethyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰,—SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O)⁻)₂(M⁺)₂,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰,—C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O) O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰ isselected from the group consisting of optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl, each R⁷⁰ is independentlyhydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, twoR^(w)s, taken together with the nitrogen atom to which they are bonded,form a 5-, 6- or 7-membered heterocycloalkyl which may optionallyinclude from 1 to 4 of the same or different additional heteroatomsselected from the group consisting of O, N and S, of which N may have —Hor C₁-C₃ alkyl substitution; and each M⁺ is a counter ion with a netsingle positive charge. Each M⁺ may independently be, for example, analkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; oran alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or[Ba²⁺]_(0.5) (“subscript 0.5 means that one of the counter ions for suchdivalent alkali earth ions can be an ionized form of a compound of theinvention and the other a typical counter ion such as chloride, or twoionized compounds disclosed herein can serve as counter ions for suchdivalent alkali earth ions, or a doubly ionized compound of theinvention can serve as the counter ion for such divalent alkali earthions). As specific examples, —NR⁸⁰R⁸⁰ is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl andN-morpholinyl.

In addition to the disclosure herein, substituent groups for hydrogenson unsaturated carbon atoms in “substituted” alkene, alkyne, aryl andheteroaryl groups are, unless otherwise specified: —R⁶⁰, halo, —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺,—OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁸⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined, provided that in case ofsubstituted alkene or alkyne, the substituents are not —O⁻M⁺, —OR⁷⁰,—SR⁷⁰, or —S⁻M⁺.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for hydrogens on nitrogen atoms in“substituted” heteroalkyl and cycloheteroalkyl groups are, unlessotherwise

specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl,—CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰, —OS(O)₂R⁷⁰,—OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰,—OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰) R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁸⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In addition to the disclosure herein, in a certain embodiment, a groupthat is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3substituents, 1 or 2 substituents, or 1 substituent.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to elicit thedesired therapeutic effect (e.g., treatment of a specified disorder ordisease or one or more of its symptoms and/or prevention of theoccurrence of the disease or disorder). In reference to polyglutaminediseases, a pharmaceutically or therapeutically effective amountincludes an amount sufficient to, among other things, prevent or cause areduction of proteinaceous deposits in the brain of a subject.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to a patient. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible.

Also of interest as active agents for use in embodiments of the methodsare prodrugs. Such prodrugs are in general functional derivatives of thecompounds that are readily convertible in vivo into the requiredcompounds. Thus, in the methods of the present disclosure, the term“administering” encompasses administering the compound specificallydisclosed or with a compound which may not be specifically disclosed,but which converts to the specified compound in vivo afteradministration to the subject in need thereof. Conventional proceduresfor the selection and preparation of suitable prodrug derivatives aredescribed, e.g., in Wermuth, “Designing Prodrugs and Bioprecursors” inWermuth, ed. The Practice of Medicinal Chemistry, 2d Ed., pp. 561-586(Academic Press 2003). Prodrugs include esters that hydrolyze in vivo(e.g., in the human body) to produce a compound described hereinsuitable for the methods and compositions of the present disclosure.Suitable ester groups include, without limitation, those derived frompharmaceutically acceptable, aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety has no more than 6 carbon atoms. Illustrativeesters include formates, acetates, propionates, butyrates, acrylates,citrates, succinates, and ethylsuccinates.

The term “sample” as used herein relates to a material or mixture ofmaterials, typically, although not necessarily, in fluid, i.e., aqueous,form, containing one or more components of interest. Samples may bederived from a variety of sources such as from food stuffs,environmental materials, a biological sample or solid, such as tissue orfluid isolated from an individual, including but not limited to, forexample, plasma, serum, spinal fluid, semen, lymph fluid, the externalsections of the skin, respiratory, intestinal, and genitourinary tracts,tears, saliva, milk, blood cells, tumors, organs, and also samples of invitro cell culture constituents (including but not limited toconditioned medium resulting from the growth of cells in cell culturemedium, putatively virally infected cells, recombinant cells, and cellcomponents). In certain embodiments of the method, the sample includes acell. In some instances of the method, the cell is in vitro. In someinstances of the method, the cell is in vivo.

Other definitions of terms may appear throughout the specification.

DETAILED DESCRIPTION

Methods of modulating the interaction between β-amyloid and α7-nAChR areprovided. Aspects of the methods include administering to the subject aneffective amount of a naphthalene derivative active agent. Compositionsand kits for practicing the subject methods are also provided. Themethods, compositions and kits find use in treating a variety ofapplications, such as treating a subject for a neurodegenerativedisease, e.g., Alzheimer's disease.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Methods

As summarized above, aspects of the present disclosure include methodsof modulating the interaction, e.g., binding, between β-amyloid andα7-nAChR. In some instances, the methods are methods of at leastreducing the binding of β-amyloid to α7-nAChR. By “at least reducing” ismeant diminishing the magnitude or amount of binding by 2-fold or more,such as 5-fold or more, including 10-fold or more, of β-amyloid toα7-nAChR, as compared to a suitable control. In some instances, themethods result in substantially if not completely inhibiting binding ofβ-amyloid to α7-nAChR.

In practicing methods according to certain embodiments, a naphthalenederivative compound, e.g., propanolol or a novel derivative thereof(such as further described below), is contacted with a cell in whichmodulation of the interaction, e.g., binding, between β-amyloid andα7-nAChR is desired. Contact may be in vitro or in vivo, as desired.Where contact is in vivo, the methods may include administering aneffective amount of a naphthalene derivative compound, e.g., propanololor a novel derivative thereof (such as further described below), to anorganism or subject in which modulation of the interaction, e.g.,binding, between β-amyloid and α7-nAChR is desired.

In some instances, the methods are methods of treating a subject for aneurodegenerative, where the methods include administering to thesubject an effective amount of naphthalene derivative compound (e.g., asdescribed herein). In certain embodiments, the methods include:administering to a subject in need thereof an effective amount of anaphthalene derivative compound to treat the subject for theneurodegenerative disease. The term “treating” or “treatment” as usedherein means the treating or treatment of a disease or medical conditionin a patient, such as a mammal (such as a human) that includes: (a)preventing the disease or medical condition from occurring, such as,prophylactic treatment of a subject; (b) ameliorating the disease ormedical condition, such as, eliminating or causing regression of thedisease or medical condition in a patient; (c) suppressing the diseaseor medical condition, for example by, slowing or arresting thedevelopment of the disease or medical condition in a patient; or (d)alleviating a symptom of the disease or medical condition in a patient.

As used herein, the terms “host”, “subject”, “individual” and “patient”are used interchangeably and refer to any mammal in need of suchtreatment according to the disclosed methods. Such mammals include,e.g., humans, ovines, bovines, equines, porcines, canines, felines,non-human primate, mice, and rats. In certain embodiments, the subjectis a non-human mammal. In some embodiments, the subject is a farmanimal. In other embodiments, the subject is a pet. In some embodiments,the subject is mammalian. In certain instances, the subject is human.Other subjects can include domestic pets (e.g., dogs and cats),livestock (e.g., cows, pigs, goats, horses, and the like), rodents(e.g., mice, guinea pigs, and rats, e.g., as in animal models ofdisease), as well as non-human primates (e.g., chimpanzees, andmonkeys).

The amount of compound administered can be determined using anyconvenient methods to be an amount sufficient to produce the desiredeffect in association with a pharmaceutically acceptable diluent,carrier or vehicle. The specifications for the unit dosage forms of thepresent disclosure will depend on the particular compound employed andthe effect to be achieved, and the pharmacodynamics associated with eachcompound in the host.

In some embodiments, an effective amount of a subject compound is anamount that ranges from about 50 ng/ml to about 50 μg/ml (e.g., fromabout 50 ng/ml to about 40 μg/ml, from about 30 ng/ml to about 20 μg/ml,from about 50 ng/ml to about 10 μg/ml, from about 50 ng/ml to about 1μg/ml, from about 50 ng/ml to about 800 ng/ml, from about 50 ng/ml toabout 700 ng/ml, from about 50 ng/ml to about 600 ng/ml, from about 50ng/ml to about 500 ng/ml, from about 50 ng/ml to about 400 ng/ml, fromabout 60 ng/ml to about 400 ng/ml, from about 70 ng/ml to about 300ng/ml, from about 60 ng/ml to about 100 ng/ml, from about 65 ng/ml toabout 85 ng/ml, from about 70 ng/ml to about 90 ng/ml, from about 200ng/ml to about 900 ng/ml, from about 200 ng/ml to about 800 ng/ml, fromabout 200 ng/ml to about 700 ng/ml, from about 200 ng/ml to about 600ng/ml, from about 200 ng/ml to about 500 ng/ml, from about 200 ng/ml toabout 400 ng/ml, or from about 200 ng/ml to about 300 ng/ml).

In some embodiments, an effective amount of a subject compound is anamount that ranges from about 10 pg to about 100 mg, e.g., from about 10pg to about 50 pg, from about 50 pg to about 150 pg, from about 150 pgto about 250 pg, from about 250 pg to about 500 pg, from about 500 pg toabout 750 pg, from about 750 pg to about 1 ng, from about 1 ng to about10 ng, from about 10 ng to about 50 ng, from about 50 ng to about 150ng, from about 150 ng to about 250 ng, from about 250 ng to about 500ng, from about 500 ng to about 750 ng, from about 750 ng to about 1 μg,from about 1 μg to about 10 μg, from about 10 μg to about 50 μg, fromabout 50 μg to about 150 μg, from about 150 μg to about 250 μg, fromabout 250 μg to about 500 μg, from about 500 μg to about 750 μg, fromabout 750 μg to about 1 mg, from about 1 mg to about 50 mg, from about 1mg to about 100 mg, or from about 50 mg to about 100 mg. The amount canbe a single dose amount or can be a total daily amount. The total dailyamount can range from 10 pg to 100 mg, or can range from 100 mg to about500 mg, or can range from 500 mg to about 1000 mg.

In some embodiments, a single dose of the subject compound isadministered. In other embodiments, multiple doses of the subjectcompound are administered. Where multiple doses are administered over aperiod of time, the compound is administered twice daily (qid), daily(qd), every other day (qod), every third day, three times per week(tiw), or twice per week (biw) over a period of time. For example, acompound is administered qid, qd, qod, tiw, or biw over a period of fromone day to about 2 years or more. For example, a compound isadministered at any of the aforementioned frequencies for one week, twoweeks, one month, two months, six months, one year, or two years, ormore, depending on various factors.

In some embodiments, the methods include co-administering thenaphthalene derivative compound with a second active agent havingtherapeutic activity with respect to the target neurodegenerativedisease. For example, a number of active agents have been shown to havesome efficacy in treating the cognitive symptoms of Alzheimer's disease(e.g., memory loss, confusion, and problems with thinking andreasoning), e.g., cholinesterase inhibitors (e.g., Donepezil,Rivastigmine, Galantamine, Tacrine), Memantine, and Vitamin E. Asanother example, a number of agents have been shown to have someefficacy in treating behavioral or psychiatric symptoms of Alzheimer'sDisease, e.g., citalopram (Celexa), fluoxetine (Prozac), paroxeine(Paxil), sertraline (Zoloft), trazodone (Desyrel), lorazepam (Ativan),oxazepam (Serax), aripiprazole (Abilify), clozapine (Clozaril),haloperidol (Haldol), olanzapine (Zyprexa), quetiapine (Seroquel),risperidone (Risperdal), and ziprasidone (Geodon).

In some aspects of the subject methods, the method further comprises thestep of measuring treatment efficacy. In some such instances, thedetermination is made by comparing the results to the results performedon the same individual at an earlier time, e.g., 2 weeks earlier, 1month earlier, 2 months earlier, 3 months earlier, 6 months earlier, 1year earlier, 2 years earlier, 5 years earlier, or 10 years earlier, ormore.

In some embodiments, the subject methods further include diagnosing anindividual as having a neurodegenerative disease, e.g., using themethods described herein or known in the art. In some embodiments, thesubject methods further comprise diagnosing an individual as having aneurodegenerative disorder, e.g., Alzheimer's disease, Parkinson'sdisease, frontotemporal dementia, progressive supranuclear palsy,Huntington's disease, amyotrophic lateral sclerosis, spinal muscularatrophy, multiple sclerosis, multi-system atrophy, glaucoma, ataxias,myotonic dystrophy, dementia, and the like. In some embodiments, thesubject methods further comprise diagnosing an individual as having adisorder such as schizophrenia, traumatic brain injury, stroke, sepsis,myocardial infarction, cancer (non-small cell lung, breast, pancreatic),autism, chronic neuropathic pain, and the like. Methods for diagnosingsuch aging-associated disorders are well-known in the art, any of whichmay be used by the ordinarily skilled artisan in diagnosing theindividual. In some embodiments, the subject methods further compriseboth diagnosing an individual as having an aging-associated disorder andas having a cognitive impairment.

The above methods find use in a variety of different applications.Certain applications are reviewed in greater detail in the Utilitysection, below.

Naphthalene Derivative Compounds

Aspects of the present disclosure include naphthalene derivativecompounds which find use in the methods of the invention, e.g., asdescribed above, including treating a subject for a neurodegenerativedisease. Naphthalene derivative compounds that may be employed inmethods of the invention include, but are not limited to, thosedescribed in U.S. Pat. No. 3,337,628; the disclosure of which is hereinincorporated by reference. In some instances, the naphthalene derivativehas the structure of formula (I):

wherein:

R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, anyof which may optionally be substituted;

R² is H or alkyl, cycloalkyl, alkenyl, alkynyl, or aralalkyl radical,any of which may optionally be substituted;

wherein R1 and R2 may joined together with the nitrogen atom to form aheterocyclic radical, which may optionally be substituted;

R³, R⁴, and R⁵ are independently H or alkyl, which may optionally besubstituted; and

Q is optional and, if present, may be halogen, alkyl, substituted alkyl,hydroxy, alkoxy, substituted alkoxy, cyano, nitro, carboxy,carboxyamide, substituted carboxyamide, —SO₃H, sulfonamide, substitutedsulfonamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycle and substituted heterocycle.

In some instances, the naphthalene derivative is propranolol, having thestructure:

In some instances, the naphthalene derivative is a compound having thestructure of formula (II):

In some instances, the naphthalene derivative is a compound having thestructure of formula (III):

In some instances, the naphthalene derivative is a compound having thestructure of formula (IV):

In some instances, the naphthalene derivative is a compound having thestructure of formula (V):

Aspects of the present disclosure include naphthalene derivativecompounds (e.g., as described herein), salts thereof (e.g.,pharmaceutically acceptable salts), and/or solvate, hydrate and/orprodrug forms thereof. In addition, it is understood that, in anycompound described herein having one or more chiral centers (e.g., the1-amino carbon center), if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. It will be appreciated that allpermutations of salts, solvates, hydrates, prodrugs and stereoisomersare meant to be encompassed by the present disclosure.

In some embodiments, the subject compounds, or a prodrug form thereof,are provided in the form of pharmaceutically acceptable salts. Compoundscontaining an amine or nitrogen containing heteraryl group may be basicin nature and accordingly may react with any number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.Acids commonly employed to form such salts include inorganic acids suchas hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid,as well as organic acids such as para-toluenesulfonic, methanesulfonic,oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoicand acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, maleate, tartrate, methanesulfonate, propanesulfonates,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hippurate,gluconate, lactobionate, and the like salts. In certain specificembodiments, pharmaceutically acceptable acid addition salts includethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and those formed with organic acids such as fumaricacid and maleic acid.

In some embodiments, the subject compounds are provided in a prodrugform. “Prodrug” refers to a derivative of an active agent that requiresa transformation within the body to release the active agent. In certainembodiments, the transformation is an enzymatic transformation. Prodrugsare frequently, although not necessarily, pharmacologically inactiveuntil converted to the active agent. “Promoiety” refers to a form ofprotecting group that, when used to mask a functional group within anactive agent, converts the active agent into a prodrug. In some cases,the promoiety will be attached to the drug via bond(s) that are cleavedby enzymatic or non enzymatic means in vivo. Any convenient prodrugforms of the subject compounds can be prepared, e.g., according to thestrategies and methods described by Rautio et al. (“Prodrugs: design andclinical applications”, Nature Reviews Drug Discovery 7, 255-270(February 2008)).

In some embodiments, the subject compounds, prodrugs, stereoisomers orsalts thereof are provided in the form of a solvate (e.g., a hydrate).The term “solvate” as used herein refers to a complex or aggregateformed by one or more molecules of a solute, e.g. a prodrug or apharmaceutically-acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include by way of example, water, methanol, ethanol,isopropanol, acetic acid, and the like. When the solvent is water, thesolvate formed is a hydrate.

Also provided are pharmaceutical preparations. Pharmaceuticalpreparations are compositions that include a naphthalene derivativecompound (e.g., as described herein) (for example one or more of thesubject compounds, either alone or in the presence of one or moreadditional active agents) present in a pharmaceutically acceptablevehicle. “Pharmaceutically acceptable vehicles” may be vehicles approvedby a regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopeia or other generally recognized pharmacopeia for usein mammals, such as humans. The term “vehicle” refers to a diluent,adjuvant, excipient, or carrier with which a compound of the presentdisclosure is formulated for administration to a mammal. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used.

When administered to a mammal, the compounds and compositions of thepresent disclosure and pharmaceutically acceptable vehicles, excipients,or diluents may be sterile. In some instances, an aqueous medium isemployed as a vehicle when the subject compound is administeredintravenously, such as water, saline solutions, and aqueous dextrose andglycerol solutions.

Pharmaceutical compositions can take the form of capsules, tablets,pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions,suspensions, emulsions, suppositories, or sustained-release formulationsthereof, or any other form suitable for administration to a mammal. Insome instances, the pharmaceutical compositions are formulated foradministration in accordance with routine procedures as a pharmaceuticalcomposition adapted for oral or intravenous administration to humans.Examples of suitable pharmaceutical vehicles and methods for formulationthereof are described in Remington: The Science and Practice ofPharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, Chapters 86, 87, 88, 91, and 92, incorporated herein byreference. The choice of excipient will be determined in part by theparticular compound, as well as by the particular method used toadminister the composition. Accordingly, there is a wide variety ofsuitable formulations of the subject pharmaceutical compositions.

Administration of the subject compounds may be systemic or local. Incertain embodiments administration to a mammal will result in systemicrelease of a compound of the present disclosure (for example, into thebloodstream). Methods of administration may include enteral routes, suchas oral, buccal, sublingual, and rectal; topical administration, such astransdermal and intradermal; and parenteral administration. Suitableparenteral routes include injection via a hypodermic needle or catheter,for example, intravenous, intramuscular, subcutaneous, intradermal,intraperitoneal, intraarterial, intraventricular, intrathecal, andintracameral injection and non-injection routes, such as intravaginalrectal, or nasal administration. In certain embodiments, the compoundsand compositions of the present disclosure are administeredsubcutaneously. In certain embodiments, the compounds and compositionsof the present disclosure are administered orally. In certainembodiments, it may be desirable to administer one or more compounds ofthe present disclosure locally to the area in need of treatment. Thismay be achieved, for example, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, said implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers.

The compounds can be formulated into preparations for injection bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives.

A subject compound may also be formulated for oral administration. Foran oral pharmaceutical formulation, suitable excipients includepharmaceutical grades of carriers such as mannitol, lactose, glucose,sucrose, starch, cellulose, gelatin, magnesium stearate, sodiumsaccharine, and/or magnesium carbonate. For use in oral liquidformulations, the composition may be prepared as a solution, suspension,emulsion, or syrup, being supplied either in solid or liquid formsuitable for hydration in an aqueous carrier, such as, for example,aqueous saline, aqueous dextrose, glycerol, or ethanol, preferably wateror normal saline. If desired, the composition may also contain minoramounts of non-toxic auxiliary substances such as wetting agents,emulsifying agents, or buffers. In some embodiments, formulationssuitable for oral administration can include (a) liquid solutions, suchas an effective amount of the compound dissolved in diluents, such aswater, or saline; (b) capsules, sachets or tablets, each containing apredetermined amount of the active ingredient, as solids or granules;(c) suspensions in an appropriate liquid; and (d) suitable emulsions.Tablet forms can include one or more of lactose, mannitol, corn starch,potato starch, microcrystalline cellulose, acacia, gelatin, colloidalsilicon dioxide, croscarmellose sodium, talc, magnesium stearate,stearic acid, and other excipients, colorants, diluents, bufferingagents, moistening agents, preservatives, flavoring agents, andpharmacologically compatible excipients. Lozenge forms can include theactive ingredient in a flavor, usually sucrose and acacia or tragacanth,as well as pastilles including the active ingredient in an inert base,such as gelatin and glycerin, or sucrose and acacia, emulsions, gels,and the like containing, in addition to the active ingredient, suchexcipients as are described herein.

The subject formulations can be made into aerosol formulations to beadministered via inhalation. These aerosol formulations can be placedinto pressurized acceptable propellants, such asdichlorodifluoromethane, propane, nitrogen, and the like. They may alsobe formulated as pharmaceuticals for non-pressured preparations such asfor use in a nebulizer or an atomizer.

In some embodiments, formulations suitable for parenteral administrationinclude aqueous and non-aqueous, isotonic sterile injection solutions,which can contain anti-oxidants, buffers, bacteriostats, and solutesthat render the formulation isotonic with the blood of the intendedrecipient, and aqueous and non-aqueous sterile suspensions that caninclude suspending agents, solubilizers, thickening agents, stabilizers,and preservatives. The formulations can be presented in unit-dose ormulti-dose sealed containers, such as ampules and vials, and can bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid excipient, for example, water, forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions can be prepared from sterile powders, granules, andtablets of the kind previously described.

Formulations suitable for topical administration may be presented ascreams, gels, pastes, or foams, containing, in addition to the activeingredient, such carriers as are appropriate. In some embodiments thetopical formulation contains one or more components selected from astructuring agent, a thickener or gelling agent, and an emollient orlubricant. Frequently employed structuring agents include long chainalcohols, such as stearyl alcohol, and glyceryl ethers or esters andoligo(ethylene oxide) ethers or esters thereof. Thickeners and gellingagents include, for example, polymers of acrylic or methacrylic acid andesters thereof, polyacrylamides, and naturally occurring thickeners suchas agar, carrageenan, gelatin, and guar gum. Examples of emollientsinclude triglyceride esters, fatty acid esters and amides, waxes such asbeeswax, spermaceti, or carnauba wax, phospholipids such as lecithin,and sterols and fatty acid esters thereof. The topical formulations mayfurther include other components, e.g., astringents, fragrances,pigments, skin penetration enhancing agents, sunscreens (e.g.,sunblocking agents), etc.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions may be provided wherein each dosage unit, forexample, teaspoonful, tablespoonful, tablet or suppository, contains apredetermined amount of the composition containing one or moreinhibitors. Similarly, unit dosage forms for injection or intravenousadministration may include the inhibitor(s) in a composition as asolution in sterile water, normal saline or another pharmaceuticallyacceptable carrier.

The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of compounds ofthe present disclosure calculated in an amount sufficient to produce thedesired effect in association with a pharmaceutically acceptablediluent, carrier or vehicle. The specifications for the novel unitdosage forms of the present disclosure depend on the particular compoundemployed and the effect to be achieved, and the pharmacodynamicsassociated with each compound in the host. In pharmaceutical dosageforms, the compounds may be administered in the form of a free base,their pharmaceutically acceptable salts, or they may also be used aloneor in appropriate association, as well as in combination, with otherpharmaceutically active compounds.

Dose levels can vary as a function of the specific compound, the natureof the delivery vehicle, and the like. Desired dosages for a givencompound are readily determinable by a variety of means. The doseadministered to an animal, particularly a human, in the context of thepresent disclosure should be sufficient to effect a prophylactic ortherapeutic response in the animal over a reasonable time frame, e.g.,as described in greater detail herein. Dosage will depend on a varietyof factors including the strength of the particular compound employed,the condition of the animal, and the body weight of the animal, as wellas the severity of the illness and the stage of the disease. The size ofthe dose will also be determined by the existence, nature, and extent ofany adverse side-effects that might accompany the administration of aparticular compound.

Where the active agent is propranolol or a derivative thereof, e.g., asdescribed above, the pharmaceutical formulation is a formulation asdescribed in U.S. Pat. Nos. 4,201,866; 4,284,648; 4,428,926; 4,460,562;4,522,804; 4,556,678; 4,600,708; 5,095,151; 5,116,867; 5,478,573;5,776,985; 5,919,828; 6,500,454; 8,367,111; 9,040,086; and 9,358,214;the disclosures of which are herein incorporated by reference.

Utility

The subject methods find use in treating, including preventing,neurodegenerative diseases and/or aging-associated impairments andconditions associated therewith, such as impairments in the cognitiveability of individuals. Examples of neurodegenerative diseases and/oraging-associated impairments and conditions include the following:

Mild cognitive impairment (M.C.I.) is a modest disruption of cognitionthat manifests as problems with memory or other mental functions such asplanning, following instructions, or making decisions that have worsenedover time while overall mental function and daily activities are notimpaired. Thus, although significant neuronal death does not typicallyoccur, neurons in the aging brain are vulnerable to sub-lethalage-related alterations in structure, synaptic integrity, and molecularprocessing at the synapse, all of which impair cognitive function.

Individuals suffering from or at risk of developing an aging-associatedcognitive impairment that will benefit from treatment with the subjectplasma-comprising blood product, e.g., by the methods disclosed herein,also include individuals of any age that are suffering from a cognitiveimpairment due to an aging-associated disorder; and individuals of anyage that have been diagnosed with an aging-associated disorder that istypically accompanied by cognitive impairment, where the individual hasnot yet begun to present with symptoms of cognitive impairment. Examplesof such aging-associated disorders include the following:

Alzheimer's disease (AD). Alzheimer's disease is a progressive,inexorable loss of cognitive function associated with an excessivenumber of senile plaques in the cerebral cortex and subcortical graymatter, which also contains b-amyloid and neurofibrillary tanglesconsisting of tau protein. The common form affects persons >60 yr old,and its incidence increases as age advances. It accounts for more than65% of the dementias in the elderly.

The cause of Alzheimer's disease is not known. The disease runs infamilies in about 15 to 20% of cases. The remaining, so-called sporadiccases have some genetic determinants. The disease has an autosomaldominant genetic pattern in most early-onset and some late-onset casesbut a variable late-life penetrance. Environmental factors are the focusof active investigation. In the course of the disease, synapses, andultimately neurons are lost within the cerebral cortex, hippocampus, andsubcortical structures (including selective cell loss in the nucleusbasalis of Meynert), locus caeruleus, and nucleus raphae dorsalis.Cerebral glucose use and perfusion is reduced in some areas of the brain(parietal lobe and temporal cortices in early-stage disease, prefrontalcortex in late-stage disease). Neuritic or senile plaques (composed ofneurites, astrocytes, and glial cells around an amyloid core) andneurofibrillary tangles (composed of paired helical filaments) play arole in the pathogenesis of Alzheimer's disease. Senile plaques andneurofibrillary tangles occur with normal aging, but they are much moreprevalent in persons with Alzheimer's disease.

Parkinson's Disease. Parkinson's Disease (PD) is an idiopathic, slowlyprogressive, degenerative CNS disorder characterized by slow anddecreased movement, muscular rigidity, resting tremor, and posturalinstability. Originally considered primarily a motor disorder, PD is nowrecognized to also affect cognition, behavior, sleep, autonomicfunction, and sensory function. The most common cognitive impairmentsinclude an impairment in attention and concentration, working memory,executive function, producing language, and visuospatial function.

In primary Parkinson's disease, the pigmented neurons of the substantianigra, locus caeruleus, and other brain stem dopaminergic cell groupsare lost. The cause is not known. The loss of substantia nigra neurons,which project to the caudate nucleus and putamen, results in depletionof the neurotransmitter dopamine in these areas. Onset is generallyafter age 40, with increasing incidence in older age groups.

Secondary parkinsonism results from loss of or interference with theaction of dopamine in the basal ganglia due to other idiopathicdegenerative diseases, drugs, or exogenous toxins. The most common causeof secondary parkinsonism is ingestion of antipsychotic drugs orreserpine, which produce parkinsonism by blocking dopamine receptors.Less common causes include carbon monoxide or manganese poisoning,hydrocephalus, structural lesions (tumors, infarcts affecting themidbrain or basal ganglia), subdural hematoma, and degenerativedisorders, including striatonigral degeneration.

Frontotemporal dementia. Frontotemporal dementia (FTD) is a conditionresulting from the progressive deterioration of the frontal lobe of thebrain. Over time, the degeneration may advance to the temporal lobe.Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for20% of pre-senile dementia cases. Symptoms are classified into threegroups based on the functions of the frontal and temporal lobesaffected: Behavioural variant FTD (bvFTD), with symptoms includelethargy and aspontaneity on the one hand, and disinhibition on theother; progressive nonfluent aphasia (PNFA), in which a breakdown inspeech fluency due to articulation difficulty, phonological and/orsyntactic errors is observed but word comprehension is preserved; andsemantic dementia (SD), in which patients remain fluent with normalphonology and syntax but have increasing difficulty with naming and wordcomprehension. Other cognitive symptoms common to all FTD patientsinclude an impairment in executive function and ability to focus. Othercognitive abilities, including perception, spatial skills, memory andpraxis typically remain intact. FTD can be diagnosed by observation ofreveal frontal lobe and/or anterior temporal lobe atrophy in structuralMRI scans.

A number of forms of FTD exist, any of which may be treated or preventedusing the subject methods and compositions. For example, one form offrontotemporal dementia is Semantic Dementia (SD). SD is characterizedby a loss of semantic memory in both the verbal and non-verbal domains.SD patients often present with the complaint of word-findingdifficulties. Clinical signs include fluent aphasia, anomia, impairedcomprehension of word meaning, and associative visual agnosia (theinability to match semantically related pictures or objects). As thedisease progresses, behavioral and personality changes are often seensimilar to those seen in frontotemporal dementia although cases havebeen described of ‘pure’ semantic dementia with few late behavioralsymptoms. Structural MRI imaging shows a characteristic pattern ofatrophy in the temporal lobes (predominantly on the left), with inferiorgreater than superior involvement and anterior temporal lobe atrophygreater than posterior.

As another example, another form of frontotemporal dementia is Pick'sdisease (PiD, also PcD). A defining characteristic of the disease isbuild-up of tau proteins in neurons, accumulating into silver-staining,spherical aggregations known as “Pick bodies”. Symptoms include loss ofspeech (aphasia) and dementia. Patients with orbitofrontal dysfunctioncan become aggressive and socially inappropriate. They may steal ordemonstrate obsessive or repetitive stereotyped behaviors. Patients withdorsomedial or dorsolateral frontal dysfunction may demonstrate a lackof concern, apathy, or decreased spontaneity. Patients can demonstratean absence of self-monitoring, abnormal self-awareness, and an inabilityto appreciate meaning. Patients with gray matter loss in the bilateralposterolateral orbitofrontal cortex and right anterior insula maydemonstrate changes in eating behaviors, such as a pathologic sweettooth. Patients with more focal gray matter loss in the anterolateralorbitofrontal cortex may develop hyperphagia. While some of the symptomscan initially be alleviated, the disease progresses and patients oftendie within two to ten years.

Huntington's disease. Huntington's disease (HD) is a hereditaryprogressive neurodegenerative disorder characterized by the developmentof emotional, behavioral, and psychiatric abnormalities; loss ofintellectual or cognitive functioning; and movement abnormalities (motordisturbances). The classic signs of HD include the development ofchorea—involuntary, rapid, irregular, jerky movements that may affectthe face, arms, legs, or trunk—as well as cognitive decline includingthe gradual loss of thought processing and acquired intellectualabilities. There may be impairment of memory, abstract thinking, andjudgment; improper perceptions of time, place, or identity(disorientation); increased agitation; and personality changes(personality disintegration). Although symptoms typically become evidentduring the fourth or fifth decades of life, the age at onset is variableand ranges from early childhood to late adulthood (e.g., 70s or 80s).

HD is transmitted within families as an autosomal dominant trait. Thedisorder occurs as the result of abnormally long sequences or “repeats”of coded instructions within a gene on chromosome 4 (4p16.3). Theprogressive loss of nervous system function associated with HD resultsfrom loss of neurons in certain areas of the brain, including the basalganglia and cerebral cortex.

Amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is arapidly progressive, invariably fatal neurological disease that attacksmotor neurons. Muscular weakness and atrophy and signs of anterior horncell dysfunction are initially noted most often in the hands and lessoften in the feet. The site of onset is random, and progression isasymmetric. Cramps are common and may precede weakness. Rarely, apatient survives 30 years; 50% die within 3 years of onset, 20% live 5years, and 10% live 10 years. Diagnostic features include onset duringmiddle or late adult life and progressive, generalized motor involvementwithout sensory abnormalities. Nerve conduction velocities are normaluntil late in the disease. Recent studies have documented thepresentation of cognitive impairments as well, particularly a reductionin immediate verbal memory, visual memory, language, and executivefunction.

A decrease in cell body area, number of synapses and total synapticlength has been reported in even normal-appearing neurons of the ALSpatients. It has been suggested that when the plasticity of the activezone reaches its limit, a continuing loss of synapses can lead tofunctional impairment. Promoting the formation or new synapses orpreventing synapse loss may maintain neuron function in these patients.

Multiple Sclerosis. Multiple Sclerosis (MS) is characterized by varioussymptoms and signs of CNS dysfunction, with remissions and recurringexacerbations. The most common presenting symptoms are paresthesias inone or more extremities, in the trunk, or on one side of the face;weakness or clumsiness of a leg or hand; or visual disturbances, e.g.,partial blindness and pain in one eye (retrobulbar optic neuritis),dimness of vision, or scotomas. Common cognitive impairments includeimpairments in memory (acquiring, retaining, and retrieving newinformation), attention and concentration (particularly dividedattention), information processing, executive functions, visuospatialfunctions, and verbal fluency. Common early symptoms are ocular palsyresulting in double vision (diplopia), transient weakness of one or moreextremities, slight stiffness or unusual fatigability of a limb, minorgait disturbances, difficulty with bladder control, vertigo, and mildemotional disturbances; all indicate scattered CNS involvement and oftenoccur months or years before the disease is recognized. Excess heat mayaccentuate symptoms and signs.

The course is highly varied, unpredictable, and, in most patients,remittent. At first, months or years of remission may separate episodes,especially when the disease begins with retrobulbar optic neuritis.However, some patients have frequent attacks and are rapidlyincapacitated; for a few the course can be rapidly progressive.

Glaucoma. Glaucoma is a common neurodegenerative disease that affectsretinal ganglion cells (RGCs). Evidence supports the existence ofcompartmentalized degeneration programs in synapses and dendrites,including in RGCs. Recent evidence also indicates a correlation betweencognitive impairment in older adults and glaucoma (Yochim B P, et al.Prevalence of cognitive impairment, depression, and anxiety symptomsamong older adults with glaucoma. J Glaucoma. 2012; 21(4):250-254).

Myotonic dystrophy. Myotonic dystrophy (DM) is an autosomal dominantmultisystem disorder characterized by dystrophic muscle weakness andmyotonia. The molecular defect is an expanded trinucleotide (CTG) repeatin the 3′ untranslated region of the myotonin-protein kinase gene onchromosome 19q. Symptoms can occur at any age, and the range of clinicalseverity is broad. Myotonia is prominent in the hand muscles, and ptosisis common even in mild cases. In severe cases, marked peripheralmuscular weakness occurs, often with cataracts, premature balding,hatchet facies, cardiac arrhythmias, testicular atrophy, and endocrineabnormalities (e.g., diabetes mellitus). Mental retardation is common insevere congenital forms, while an aging-related decline of frontal andtemporal cognitive functions, particularly language and executivefunctions, is observed in milder adult forms of the disorder. Severelyaffected persons die by their early 50s.

Dementia. Dementia describes class of disorders having symptomsaffecting thinking and social abilities severely enough to interferewith daily functioning. Other instances of dementia in addition to thedementia observed in later stages of the aging-associated disordersdiscussed above include vascular dementia, and dementia with Lewybodies, described below.

In vascular dementia, or “multi-infarct dementia”, cognitive impairmentis caused by problems in supply of blood to the brain, typically by aseries of minor strokes, or sometimes, one large stroke preceded orfollowed by other smaller strokes. Vascular lesions can be the result ofdiffuse cerebrovascular disease, such as small vessel disease, or focallesions, or both. Patients suffering from vascular dementia present withcognitive impairment, acutely or subacutely, after an acutecerebrovascular event, after which progressive cognitive decline isobserved. Cognitive impairments are similar to those observed inAlzheimer's disease, including impairments in language, memory, complexvisual processing, or executive function, although the related changesin the brain are not due to AD pathology but to chronic reduced bloodflow in the brain, eventually resulting in dementia. Single photonemission computed tomography (SPECT) and positron emission tomography(PET) neuroimaging may be used to confirm a diagnosis of multi-infarctdementia in conjunction with evaluations involving mental statusexamination.

Dementia with Lewy bodies (DLB, also known under a variety of othernames including Lewy body dementia, diffuse Lewy body disease, corticalLewy body disease, and senile dementia of Lewy type) is a type ofdementia characterized anatomically by the presence of Lewy bodies(clumps of alpha-synuclein and ubiquitin protein) in neurons, detectablein post mortem brain histology. Its primary feature is cognitivedecline, particularly of executive functioning. Alertness and short termmemory will rise and fall. Persistent or recurring visual hallucinationswith vivid and detailed pictures are often an early diagnostic symptom.DLB it is often confused in its early stages with Alzheimer's diseaseand/or vascular dementia, although, where Alzheimer's disease usuallybegins quite gradually, DLB often has a rapid or acute onset. DLBsymptoms also include motor symptoms similar to those of Parkinson's.DLB is distinguished from the dementia that sometimes occurs inParkinson's disease by the time frame in which dementia symptoms appearrelative to Parkinson symptoms. Parkinson's disease with dementia (PDD)would be the diagnosis when dementia onset is more than a year after theonset of Parkinson's. DLB is diagnosed when cognitive symptoms begin atthe same time or within a year of Parkinson symptoms.

Progressive supranuclear palsy. Progressive supranuclear palsy (PSP) isa brain disorder that causes serious and progressive problems withcontrol of gait and balance, along with complex eye movement andthinking problems. One of the classic signs of the disease is aninability to aim the eyes properly, which occurs because of lesions inthe area of the brain that coordinates eye movements. Some individualsdescribe this effect as a blurring. Affected individuals often showalterations of mood and behavior, including depression and apathy aswell as progressive mild dementia. The disorder's long name indicatesthat the disease begins slowly and continues to get worse (progressive),and causes weakness (palsy) by damaging certain parts of the brain abovepea-sized structures called nuclei that control eye movements(supranuclear). PSP was first described as a distinct disorder in 1964,when three scientists published a paper that distinguished the conditionfrom Parkinson's disease. It is sometimes referred to asSteele-Richardson-Olszewski syndrome, reflecting the combined names ofthe scientists who defined the disorder. Although PSP gets progressivelyworse, no one dies from PSP itself.

Ataxia. People with ataxia have problems with coordination because partsof the nervous system that control movement and balance are affected.Ataxia may affect the fingers, hands, arms, legs, body, speech, and eyemovements. The word ataxia is often used to describe a symptom ofincoordination which can be associated with infections, injuries, otherdiseases, or degenerative changes in the central nervous system. Ataxiais also used to denote a group of specific degenerative diseases of thenervous system called the hereditary and sporadic ataxias which are theNational Ataxia Foundation's primary emphases.

Multiple-system atrophy. Multiple-system atrophy (MSA) is a degenerativeneurological disorder. MSA is associated with the degeneration of nervecells in specific areas of the brain. This cell degeneration causesproblems with movement, balance, and other autonomic functions of thebody such as bladder control or blood-pressure regulation. The cause ofMSA is unknown and no specific risk factors have been identified. Around55% of cases occur in men, with typical age of onset in the late 50s toearly 60s. MSA often presents with some of the same symptoms asParkinson's disease. However, MSA patients generally show minimal if anyresponse to the dopamine medications used for Parkinson's.

In some embodiments, the subject methods find use in treating individualas having a disorder such as schizophrenia, traumatic brain injury,stroke, sepsis, myocardial infarction, cancer (non-small cell lung,breast, pancreatic), autism, chronic neuropathic pain, and the like.

In some embodiments, the subject methods and compositions find use inslowing the progression of the target condition. In some instances,cognitive abilities in the individual will decline more slowly followingtreatment by the disclosed methods than prior to or in the absence oftreatment by the disclosed methods. In some such instances, the subjectmethods of treatment include measuring the progression of cognitivedecline after treatment, and determining that the progression ofcognitive decline is reduced. In some such instances, the determinationis made by comparing to a reference, e.g., the rate of cognitive declinein the individual prior to treatment, e.g., as determined by measuringcognition prior at two or more time points prior to administration ofthe subject blood product.

The subject methods and compositions also find use in stabilizing thecognitive abilities of an individual, e.g., an individual suffering fromaging-associated cognitive decline or an individual at risk of sufferingfrom aging-associated cognitive decline. For example, the individual maydemonstrate some aging-associated cognitive impairment, and progressionof cognitive impairment observed prior to treatment with the disclosedmethods will be halted following treatment by the disclosed methods. Asanother example, the individual may be at risk for developing anaging-associated cognitive decline (e.g., the individual may be aged 50years old or older, or may have been diagnosed with an aging-associateddisorder), and the cognitive abilities of the individual aresubstantially unchanged, i.e., no cognitive decline can be detected,following treatment by the disclosed methods as compared to prior totreatment with the disclosed methods.

The subject methods and compositions also find use in reducing cognitiveimpairment in an individual suffering from an aging-associated cognitiveimpairment. In other words, cognitive ability is improved in theindividual following treatment by the subject methods. For example, thecognitive ability in the individual is increased, e.g., by 2-fold ormore, 5-fold or more, 10-fold or more, 15-fold or more, 20-fold or more,30-fold or more, or 40-fold or more, including 50-fold or more, 60-foldor more, 70-fold or more, 80-fold or more, 90-fold or more, or 100-foldor more, following treatment by the subject methods relative to thecognitive ability that is observed in the individual prior to treatmentby the subject methods. In some instances, treatment by the subjectmethods and compositions restores the cognitive ability in theindividual suffering from aging-associated cognitive decline, e.g., totheir level when the individual was about 40 years old or less. In otherwords, cognitive impairment is abrogated.

Combination Therapies

The subject compounds can be administered to a subject alone or incombination with an additional, i.e., second, active agent, as indicatedabove. As such, in some cases, the subject method further comprisesadministering to the subject at least one additional compound. Anyconvenient agents may be utilized, including compounds useful fortreating viral infections. The terms “agent,” “compound,” and “drug” areused interchangeably herein. For example, naphthalene derivativecompounds can be administered alone or in conjunction with one or moreother drugs, such as drugs employed in the treatment ofneurodegenerative disease conditions. In some embodiments, the methodfurther includes coadministering concomitantly or in sequence a secondagent. Second agents of interest include, but are not limited to,cholinesterase inhibitors (e.g., Donepezil, Rivastigmine, Galantamine,Tacrine), Memantine, and Vitamin E. As another example, a number ofagents have been shown to have some efficacy in treating behavioral orpsychiatric symptoms of Alzheimer's Disease, e.g., citalopram (Celexa),fluoxetine (Prozac), paroxeine (Paxil), sertraline (Zoloft), trazodone(Desyrel), lorazepam (Ativan), oxazepam (Serax), aripiprazole (Abilify),clozapine (Clozaril), haloperidol (Haldol), olanzapine (Zyprexa),quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone(Geodon).

The terms “co-administration” and “in combination with” include theadministration of two or more therapeutic agents either simultaneously,concurrently or sequentially within no specific time limits. In oneembodiment, the agents are present in the cell or in the subjects bodyat the same time or exert their biological or therapeutic effect at thesame time. In one embodiment, the therapeutic agents are in the samecomposition or unit dosage form. In other embodiments, the therapeuticagents are in separate compositions or unit dosage forms. In certainembodiments, a first agent can be administered prior to (e.g., minutes,15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours,12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of asecond therapeutic agent.

“Concomitant administration” of a known therapeutic drug with apharmaceutical composition of the present disclosure meansadministration of the compound and second agent at such time that boththe known drug and the composition of the present invention will have atherapeutic effect. Such concomitant administration may involveconcurrent (i.e. at the same time), prior, or subsequent administrationof the drug with respect to the administration of a subject compound.Routes of administration of the two agents may vary, whererepresentative routes of administration are described in greater detailbelow. A person of ordinary skill in the art would have no difficultydetermining the appropriate timing, sequence and dosages ofadministration for particular drugs and compounds of the presentdisclosure.

In some embodiments, the compounds (e.g., a subject compound and the atleast one additional compound) are administered to the subject withintwenty-four hours of each other, such as within 12 hours of each other,within 6 hours of each other, within 3 hours of each other, or within 1hour of each other. In certain embodiments, the compounds areadministered within 1 hour of each other. In certain embodiments, thecompounds are administered substantially simultaneously. By administeredsubstantially simultaneously is meant that the compounds areadministered to the subject within about 10 minutes or less of eachother, such as 5 minutes or less, or 1 minute or less of each other.

Also provided are pharmaceutical preparations of the subject compoundsand the second active agent. In pharmaceutical dosage forms, thecompounds may be administered in the form of their pharmaceuticallyacceptable salts, or they may also be used alone or in appropriateassociation, as well as in combination, with other pharmaceuticallyactive compounds.

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg ofbody weight per day are useful in representative embodiments, oralternatively about 0.5 mg to about 7 g per patient per day. Those ofskill will readily appreciate that dose levels can vary as a function ofthe specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Dosages for a givencompound are readily determinable by those of skill in the art by avariety of means.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient, such as 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

As such, unit dosage forms for oral or rectal administration such assyrups, elixirs, and suspensions may be provided wherein each dosageunit, for example, teaspoonful, tablespoonful, tablet or suppository,contains a predetermined amount of the composition containing one ormore inhibitors. Similarly, unit dosage forms for injection orintravenous administration may include the inhibitor(s) in a compositionas a solution in sterile water, normal saline or anotherpharmaceutically acceptable carrier. The term “unit dosage form,” asused herein, refers to physically discrete units suitable as unitarydosages for human and animal subjects, each unit containing apredetermined quantity of compounds of the present invention calculatedin an amount sufficient to produce the desired effect in associationwith a pharmaceutically acceptable diluent, carrier or vehicle. Thespecifications for the novel unit dosage forms of the present inventiondepend on the particular peptidomimetic compound employed and the effectto be achieved, and the pharmacodynamics associated with each compoundin the host. Those of skill in the art will readily appreciate that doselevels can vary as a function of the specific compound, the nature ofthe delivery vehicle, and the like. Preferred dosages for a givencompound or agent are readily determinable by those of skill in the artby a variety of means.

Kits & Systems

Also provided are kits and systems that find use in practicingembodiments of the methods, such as those described as described above.The term “system” as employed herein refers to a collection of two ormore different active agents, present in a single or disparatecomposition, that are brought together for the purpose of practicing thesubject methods. The term kit refers to a packaged active agent oragents. In some embodiments, the subject system or kit includes a doseof a subject naphthalene derivative compound (e.g., as described herein)and a dose of a second active agent (e.g., as described herein) inamounts effective to treat a subject for a target disease or condition.

In addition to the above-mentioned components, a subject kits mayfurther include instructions for using the components of the kit, e.g.,to practice the subject method. The instructions are generally recordedon a suitable recording medium. For example, the instructions may beprinted on a substrate, such as paper or plastic, etc. As such, theinstructions may be present in the kits as a package insert, in thelabeling of the container of the kit or components thereof (i.e.,associated with the packaging or sub-packaging) etc. In otherembodiments, the instructions are present as an electronic storage datafile present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, Hard Disk Drive (HDD), portable flash drive, etc. Inyet other embodiments, the actual instructions are not present in thekit, but means for obtaining the instructions from a remote source, e.g.via the internet, are provided. An example of this embodiment is a kitthat includes a web address where the instructions can be viewed and/orfrom which the instructions can be downloaded. As with the instructions,this means for obtaining the instructions is recorded on a suitablesubstrate.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES I. Introduction

In this study we screened and assessed FDA approved drugs for PAMactivity in vitro at the α7 nAChR. We also created structurally novelderivatives of one of the drugs, propranolol.

II. METHODS A. Pharmacophore Modeling

A common feature pharmacophore was developed based on galantamine usingcommercially available software (Discovery Studio vers 4.1, Biovia, SanDiego, Calif.), as described in detail in Ekins et al.,“alpha7-Nicotinic acetylcholine receptor inhibition by indinavir:implications for cognitive dysfunction in treated HIV disease,” AIDS(May 15, 2017) 31: 1083-1089. Briefly, we started by using galantamineas the template of a common feature pharmacophore model and this wasthen used to search a 3D database of FDA approved drugs and commerciallyavailable compounds. (Motel et al., “Cholinergic modulation by opioidreceptor ligands: potential application to Alzheimer's disease,” MiniRev Med Chem (2013) 13: 456-466.

B. In Vitro Patch-Clamp Assay for PAM Activity at the α7 nAChR

The in vitro patch-clamp assay for PAM activity at the α7 nAChR wasperformed with PNU-120596 as a positive control. All patch-clamp testingwas performed by an independent contract research company, ChanTest(Charles River) in the USA. For patch-clamp measurements, recordings ofcurrents through α7 nAChR were made in a blinded fashion. Measurementsof concentration-response and rate-dependence of test articles on α7nAChR activation kinetics were performed with data collected. Thesignificance of test article effects were evaluated versus parallelvehicle and positive control (PNU-120596) recordings. For all of thecompounds, a dose response curve over the range of concentrations testedwas then generated.

Test article effects were evaluated in 8-point concentration-responseformat (4 replicate wells/concentration). All test and control solutionscontained 0.3% DMSO. The test article formulations were loaded in a384-well compound plate using an automated liquid handling system(SciClone ALH3000, Caliper LifeScienses). To verify the sensitivity ofthe assay, the standard agonist positive control article—PNU-120596(PAM) was applied at 8 concentrations, 4 replicates per concentration.

CHO cells (ATCC, Manassas, Va.) were maintained in tissue cultureincubators per ChanTest SOP. Stocks were maintained in cryogenicstorage. Cells used for electrophysiology were plated in 150-mm plasticculture dishes. CHO cells were transfected with the appropriate ionchannel or receptor cDNA(s). Cells were cultured in Ham's F-12supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium,100 μg/mL streptomycin sulfate, and the appropriate selectionantibiotics.

The effects were evaluated using IonWorks™ Barracuda system (MDC) usingthe following electrophysiological procedures: Intracellular solution(mM) consisted off 90 CsF, 50 CsCl, 2 MgCl₂, 5 EGTA 10 HEPES, adjustedto pH 7.2 with CsOH. In preparation for a recording session, theintracellular solution was loaded into the intracellular compartment ofthe PPC planar electrode. Extracellular solution, HB-PS (composition inmM) consisted of 137 NaCl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 HEPES, 10glucose; pH 7.4 adjusted with NaOH. The holding potential was −70 mV.Extracellular buffer was loaded into the PPC plate wells (11 uL perwell). Cell suspension was pipetted into the wells (9 uL per well) ofthe PPC planar electrode. Whole-cell recording configuration wasestablished via patch perforation with membrane currents recorded byon-board patch clamp amplifiers. One recording was performed duringapplication of test articles to detect agonist effects or duringco-application of test articles with 1 mM acetylcholine to detectmodulation effects. The application consisted of the addition of 20 μLof 1× concentrated test article solution and agonist at 20 uL/s (1second total application time).

PAM effect of test articles on the channel was calculated as: %activation=(I_(TA)/I_(AC))×100%, where I_(TA) was the current elicitedwith 1000 uM Acetylcholine in the presents of I_(TA) and I_(AC) was theaveraged current elicited with the 1000 uM Acetylcholine with 0.3% DMSO

C. Design of Structurally Novel Propranolol Derivatives

The 3-D structure for the α7-nAChR has not yet been determined,consequently we used acetylcholine binding protein as a substitute forthe computer based binding affinity simulations. The 3-D structure ofacetylcholine binding protein was downloaded from the National ProteinData Bank (www.rcsb.org) and the 3-D structure for propranolol wasdownloaded from DrugBank.ca.gov. An exhaustive set of potentialderivatives was then created by systematically replacing single hydrogenatoms in propranolol with either a methyl, hydroxyl, or carbonyl groupat all possible locations along the carbon chain of the molecule usingthe commercially available program Visual Molecular Dynamics (VMD,available at http://www.ks.uiuc.edu/Research/vmd/). A secondcommercially available program, PyRx (available athttp://pyrx.sourceforge.net/), was then used to determine the predictedbinding affinities between individual derivatives and the α7-nAChR.

D. Synthesis of Structurally Novel Propranolol Derivatives

Synthesis of structurally novel propranolol derivatives was performed bya contract research company (BioFocus, Inc., United Kingdom). Thestructures for all compounds synthesized were confirmed through threemethods: high-performance liquid chromatography (HPLC), massspectroscopy (MS), and nuclear magnetic resonance (NMR) studies.

III. Results A. Virtual Screen

The pharmacophore based on galantamine consisted of two hydrophobicfeatures, a hydrogen bond acceptor, a hydrogen bond donor, and apositive ionizabile feature. After screening over 1000 molecules, over160 remaining molecules that mapped to the pharmacophore were filteredto identify potentially repurposable α7-nAChR PAMs. Molecules thatmapped well to the features of either pharmacophore were identified andknown PAMs or problematic compounds were removed. The selected compounds(Table 1) were then tested in vitro.

TABLE 1 EC₅₀ (IC₅₀) values of Test Articles TA EC₅₀ (IC₅₀), μM # TA IDPeak 0.5-AUC 1 Carvedilol (18.9) (4.4) 2 Alfuzosin hydrochloride (22.9)(14.2)  3 Riboflavin ND ND 4 Bromocriptine ND (66.1)  5 Propanolol(15.9) (5.3) 6 Fexofenadine ND ND 7 O-Desmethyl Galantamine ND ND 8N-Desmethyl Galantamine ND ND 9 Galantamine hydrobromide ND ND PCPNU-120596   1.066  1.215

B. Patch Clamp Studies of FDA Approved Compounds and GalantamineDerivatives

Three compounds, riboflavin, bromocriptine, and propranolol, wereidentified as displaying PAM effects at the α7-nAChR (FIG. 1) inaddition to galantamine and two galantamine derivatives that displayedmeasurable α7-nAChR PAM activity at lower concentrations (see FIG. 1).Furthermore, three compounds, carvedilol, alfuzosin hydrochloride, andpropranolol, were identified as showing inhibitor effects at theα7-nAChR (See Table 1, above). The 1050 value was greatest for alfuzosin(1050=22.9), followed by carvedilol (1050=18.9), and was lowest forpropranolol (1050=15.9).

Not only did propranolol yield a magnitude of the PAM effect on α7-nAChRthat was much lower than that of the commercially available PAM compoundthat was used as a positive control PNU-120596, (see FIG. 2), but italso displayed evidence of functional inhibition at higherconcentrations (see FIG. 2). Functional inhibition is not seen with mostother commercial α7-nAChR compounds, including PNU-120596 which does notdisplay any evidence of functional inhibition (see FIG. 2)

C. Binding Affinity Studies of Propranolol Modifications

Binding affinity calculations for all possible propranolol modificationsconsisting of addition of either methyl, hydroxyl, or carboxyl groupsalong the carbon chain of the molecule were calculated using PyRx andgraphed relative to the position of the modification in the molecule(See FIG. 3). While multiple types and locations of modifications wereable to increase the binding affinity with the α7-nAChR, we selected 4structures to synthesize, including one structure (derivative 6) forwhich two stereoisomers were possible. For derivative 6 we decided tohave both enantiomers (R and S) synthesized and tested. The structuresare summarized in Table 2.

TABLE 2 Chemical Formula and Molecular Weight of the PropranololDerivatives Compound Formula Weight BF000825289 (V2) C16H21NO3 275.34BF000825198 (V4) C17H23NO2 273.37 BF000825197 (V5) C17H23NO2 273.37BF000825199 (V6_R) C17H23NO2 273.37 BF000825200 (V6_S) C17H23NO2 273.37

The structures are shown below:

D. Patch Clamp Studies of Structurally Novel Propranolol Derivatives

Of the five structurally novel propranolol derivatives tested, four(Derivative 2, 4, 6S, and 6R) displayed PAM effects at the α7-nAChR (SeeFIG. 4). All of the structurally novel propranolol derivatives thatdisplayed α7 nAChR PAM activity not only had milder magnitudes of effectthan PNU-120596 (similar to the magnitude of effect displayed bypropranolol and galantamine), but these compounds also all displayed amore physiologically normal effect at the α7 nAChR that includedfunctional inhibition at higher concentrations (See FIG. 4).

IV. Discussion

Current therapies for Alzheimer's disease are less than optimal as theyare purely symptomatic with no disease modifying effect. To date thereare no medications available that target the underlyinghistopathological changes associated with the disease: formation ofβ-amyloid and tau protein aggregates. The α7-nAChR agonists comprise oneclass of compounds that are potentially disease modifying throughdisruption of the interaction between β-amyloid and α7-nAChR.Consequently, developing novel compounds that act through this mechanismand are well tolerated is an active area of research for creatingpotential new therapeutic agents in AD. In this study, we identifiedcommercially available compounds with previously unknown α7-nAChR PAMfunctionality. For one compound, propranolol, we created fourstructurally novel derivatives that displayed α7-nAChR PAM functionalityas well as functional inhibition. Further testing of propranolol—as wellas all compounds with α7-nAChR PAM functionality—in vivo for possibledevelopment as new therapeutic agents for the treatment of AD is likelywarranted based on these preliminary studies.

Propranolol is particularly well suited for potential repurposing as anα7-nAChR PAM, as it is already FDA approved for treatment of a varietyof medical disorders in the United States (high blood pressure,irregular heartbeat, essential tremors, anxiety, etc.) and has a longhistory of use in many countries. In general, propranolol is consideredto be a safe medication that requires no blood-test monitoring, hasminimal side effects, typically doses well below toxic levels, and isusually well tolerated. The medication is well known to act as anon-selective n-blocker without sympathomimetic activity. It also hasmembrane stabilizing activity, and is highly lipid soluble which—whencoupled with its small molecular weight—allows for good blood brainbarrier penetration. We feel this medication is ideal for repurposingand, consequently, further testing in patients suffering fromAlzheimer's disease is urgently needed.

The usefulness of a well-tolerated and effective α7-nAChR PAM compoundwill extend beyond treatment of Alzheimer's disease. For instance,δ-amyloid and tau protein deposition have been implicated in thepathogenesis of several other neurodegenerative disorders which,therefore, may also be amenable to treatment with α7-nAChR agonistcompounds. Relatively common and currently untreatabledisorders—schizophrenia and dementia in Parkinson's disease inparticular—are targets for treatment with α7-nAChR PAMs. (Wang et al.,“β-amyloid (1-42) binds to alpha7 nicotinic acetylcholine receptor withhigh affinity. Implications for Alzheimer's disease pathology,” J BiolChem (2000) 275: 5626-5632). The compounds described herein may be usedfor treatment of such diseases.

Several α7-nAChR PAM compounds have been developed by variouspharmaceutical companies and have gone on to clinical trials, including:A-582941(2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;Abbott Laboratories), ABT-107(5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole;Abbott Laboratories), EVP-6124 (Elan Pharmaceuticals, Dublin, Ireland),SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b0]-dipyr-role-1 (2H)-carboxamide), PNU-120596(1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; GSKPharmaceuticals), Encenicline(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide; ForumPharmaceuticals).

These compounds, which possessed in vitro activity similar in magnitudeto PNU-120596 without functional inhibition, have been tried in variousPhase 1-3 clinical trials but none have been able to demonstrate a cleardisease modifying effect. Additionally, in September 2015 the FDA placeda clinical hold on three Phase 3 studies of an α7-nAChR PAM inAlzheimer's disease (still in place and further clinical research withthese compounds is currently prohibited) and one Phase 1 study inschizophrenia (later partially lifted). Anon (2015) Encenicline. Theclinical hold was specific to the compound being studied (Encenicline)and its severe gastrointestinal side effect that occurs due tooverstimulation of nicotinic receptors. Anon (2015) Encenicline. Theother clinical trials of α7-nAChR PAM compounds have all failed due tolack of efficacy and are no longer being developed as potential newdrugs.

The failure of α7-nAChR PAM compounds in clinical trials due either toan inability to demonstrate meaningful clinical benefit or to seriousadverse events has been a large set back in the field, delaying theintroduction of this class of potential therapeutic compounds to themarket. These failures have been attributed in part to excessiveoverstimulation of the α7-nAChR which then causes neuronalexcitotoxicity (Guerra-Alvarez et al., “Positive allosteric modulationof alpha-7 nicotinic receptors promotes cell death by inducing Ca(2+)release from the endoplasmic reticulum,” J Neurochem (2015) 133:309-319). In general, the α7-nAChR PAM compounds that have been testedin clinical trials—and have failed—demonstrated a current across thereceptor in in vitro studies that was augmented by as much as 6,000% ofnormal (Id.). From compounds with similar activity profiles, suchstimulation of neuronal nAChRs has been shown to induce neuronal celldeath through excitotoxicity (Id.). Consequently, an α7-nAChR PAMcompound with a more modest effect, such as that demonstrated bypropranolol, offers a therapeutic alternative that finally realizes thepotential benefits of α7-nAChR PAM compounds in AD without causingadverse events related to overstimulation of the α7-nAChR.

V. Conclusion

In this study we have identified previously unknown α7 nAChR PAMactivity in vitro for several FDA approved medications, includingpropranolol. When compared to other α7 nAChR PAM compounds that havefailed in clinical trials, propranolol possesses a milder and morephysiologically normal augmentation of current across the α7 nAChR. Themilder α7 nAChR PAM effect of propranolol allows for it to exhibit thepositive and beneficial aspects related to disruption of interactionsbetween the α7 nAChR and β-amyloid protein without resulting in adverseevents related to excessive overstimulation of the α7 nAChR. We alsodesigned structurally novel propranolol derivatives with α7 nAChR PAMactivity.

Notwithstanding the appended clauses, the disclosure is also defined bythe following clauses:

1. A method of modulating the interaction between β-amyloid and α7-nAChRin a cell, the method comprising:

contacting the cell with a naphthalene derivative to modulate theinteraction between β-amyloid and α7-nAChR in the cell.

2. The method according to Clause 1, wherein naphthalene derivative hasthe structure of formula (I):

wherein:

R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, anyof which may optionally be substituted;

R² is H or alkyl, cycloalkyl, alkenyl, alkynyl, or aralalkyl radical,any of which may optionally be substituted;

wherein R1 and R2 may joined together with the nitrogen atom to form aheterocyclic radical, which may optionally be substituted;

R³, R⁴, and R⁵ are independently H or alkyl, which may optionally besubstituted; and

Q is optional and, if present, may be halogen, alkyl, substituted alkyl,hydroxy, alkoxy, substituted alkoxy, cyano, nitro, carboxy,carboxyamide, substituted carboxyamide, —SO₃H, sulfonamide, substitutedsulfonamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycle and substituted heterocycle.

3. The method according to Clause 2, wherein the naphthalene derivativeis propanolol.4. The method according to Clause 2, wherein the naphthalene derivativehas the structure selected from the group consisting of:

5. The method according to any of the preceding clauses, wherein thecell is in vitro.6. The method according to any of the preceding clauses, wherein thecell is in vivo.7. A method of treating a subject for a neurodegenerative disease, themethod comprising:

administering to a subject an effective amount of a naphthalenederivative to treat the subject for the neurodegenerative disease.

8. The method according to Clause 7, wherein naphthalene derivative hasthe structure of formula (I):

wherein:

R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, anyof which may optionally be substituted;

R² is H or alkyl, cycloalkyl, alkenyl, alkynyl, or aralalkyl radical,any of which may optionally be substituted;

wherein R1 and R2 may joined together with the nitrogen atom to form aheterocyclic radical, which may optionally be substituted;

R³, R⁴, and R⁵ are independently H or alkyl, which may optionally besubstituted; and

Q is optional and, if present, may be halogen, alkyl, substituted alkyl,hydroxy, alkoxy, substituted alkoxy, cyano, nitro, carboxy,carboxyamide, substituted carboxyamide, —SO₃H, sulfonamide, substitutedsulfonamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycle and substituted heterocycle.

9. The method according to Clause 8, wherein the naphthalene derivativeis propanolol.10. The method according to Clause 8, wherein the naphthalene derivativehas the structure selected from the group consisting of:

11. The method according to any of Clause 7 to 10, wherein theneurodegenerative disease is selected from the group consisting of:Alzheimer's disease, Parkinson's disease, frontotemporal dementia,progressive supranuclear palsy, Huntington's disease, amyotrophiclateral sclerosis, spinal muscular atrophy, multiple sclerosis,multi-system atrophy, glaucoma, ataxias, myotonic dystrophy anddementia.12. The method according to Clause 11, wherein the neurodegenerativedisease is Alzheimer's disease.13. The method according to any of Clauses 7 to 12, wherein the subjectis a mammal.14. The method according to Clause 13, wherein the subject is a human.15. A pharmaceutical composition comprising:

a) a naphthalene derivative selected from the group consisting of:

b) a pharmaceutical delivery vehicle.

16. The pharmaceutical composition according to Clause 15, wherein thenaphthalene derivative has the structure of formula (II):

17. The pharmaceutical composition according to Clause 15, wherein thenaphthalene derivative has the structure of formula (III):

18. The pharmaceutical composition according to Clause 15, wherein thenaphthalene derivative has the structure of formula (IV):

19. The pharmaceutical composition according to Clause 15, wherein thenaphthalene derivative has the structure of formula (V):

20. A kit comprising:

a dose of a naphthalene derivative compound; and

a dose of a second active agent having neurodegenerative diseasetherapeutic activity.

21. The kit according to Clause 20, wherein the naphthalene derivativehas the structure of formula (I):formula (I):

wherein:

R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoyl radical, anyof which may optionally be substituted;

R² is H or alkyl, cycloalkyl, alkenyl, alkynyl, or aralalkyl radical,any of which may optionally be substituted;

wherein R1 and R2 may joined together with the nitrogen atom to form aheterocyclic radical, which may optionally be substituted;

R³, R⁴, and R⁵ are independently H or alkyl, which may optionally besubstituted; and

Q is optional and, if present, may be halogen, alkyl, substituted alkyl,hydroxy, alkoxy, substituted alkoxy, cyano, nitro, carboxy,carboxyamide, substituted carboxyamide, —SO₃H, sulfonamide, substitutedsulfonamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycle and substituted heterocycle.

22. The kit according to Clause 20, wherein the naphthalene derivativeis propanolol.23. The kit according to Clause 20, wherein a naphthalene derivative isselected from the group consisting of:

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A method of modulating the interaction betweenβ-amyloid and α7-nAChR in a cell, the method comprising: contacting thecell with a naphthalene derivative to modulate the interaction betweenβ-amyloid and α7-nAChR in the cell.
 2. The method according to claim 1,wherein naphthalene derivative has the structure of formula (I):

wherein: R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoylradical, any of which may optionally be substituted; R² is H or alkyl,cycloalkyl, alkenyl, alkynyl, or aralalkyl radical, any of which mayoptionally be substituted; wherein R1 and R2 may joined together withthe nitrogen atom to form a heterocyclic radical, which may optionallybe substituted; R³, R⁴, and R⁵ are independently H or alkyl, which mayoptionally be substituted; and Q is optional and, if present, may behalogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy,cyano, nitro, carboxy, carboxyamide, substituted carboxyamide, —SO₃H,sulfonamide, substituted sulfonamide, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycle and substitutedheterocycle.
 3. The method according to claim 2, wherein the naphthalenederivative is propanolol.
 4. The method according to claim 2, whereinthe naphthalene derivative has the structure selected from the groupconsisting of:


5. The method according to any of the preceding claims, wherein themethod is a method of treating a subject for a neurodegenerativedisease.
 6. The method according to claim 5, wherein theneurodegenerative disease is selected from the group consisting of:Alzheimer's disease, Parkinson's disease, frontotemporal dementia,progressive supranuclear palsy, Huntington's disease, amyotrophiclateral sclerosis, spinal muscular atrophy, multiple sclerosis,multi-system atrophy, glaucoma, ataxias, myotonic dystrophy anddementia.
 7. The method according to claim 6, wherein theneurodegenerative disease is Alzheimer's disease.
 8. The methodaccording to any of claims 5 to 7, wherein the subject is a mammal. 9.The method according to claim 8, wherein the subject is a human.
 10. Apharmaceutical composition comprising: a) a naphthalene derivativeselected from the group consisting of:

and b) a pharmaceutical delivery vehicle.
 11. A kit comprising: a doseof a naphthalene derivative compound; and a dose of a second activeagent having neurodegenerative disease therapeutic activity.
 12. The kitaccording to claim 11, wherein the naphthalene derivative has thestructure of formula (I): formula (I):

wherein: R¹ is H or alkyl, cycloalkyl, alkenyl, aralkyl or alkanoylradical, any of which may optionally be substituted; R² is H or alkyl,cycloalkyl, alkenyl, alkynyl, or aralalkyl radical, any of which mayoptionally be substituted; wherein R1 and R2 may joined together withthe nitrogen atom to form a heterocyclic radical, which may optionallybe substituted; R³, R⁴, and R⁵ are independently H or alkyl, which mayoptionally be substituted; and Q is optional and, if present, may behalogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy,cyano, nitro, carboxy, carboxyamide, substituted carboxyamide, —SO₃H,sulfonamide, substituted sulfonamide, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycle and substitutedheterocycle.
 13. The kit according to claim 12, wherein the naphthalenederivative is propanolol.
 14. The kit according to claim 12, wherein anaphthalene derivative is selected from the group consisting of: